Metabolic syndrome (also known as “syndrome X,” “dysmetabolic syndrome,” “obesity syndrome,” “Reaven's syndrome” and interchangeably referred to herein as the “syndrome”) has emerged as a growing problem. For example, metabolic syndrome has become increasingly common in the United States. It is estimated that about 47 million adults in the United States have the syndrome.
Metabolic syndrome is generally a constellation of metabolic disorders that all result from, or are associated with, a primary disorder of insulin resistance. Accordingly, the syndrome is sometimes referred to as “insulin resistance syndrome.” Insulin resistance is characterized by disorders in which the body cannot use insulin efficiently and the body's tissues do not respond normally to insulin. As a result, insulin levels become elevated in the body's attempt to overcome the resistance to insulin. The elevated insulin levels lead, directly or indirectly, to the other metabolic abnormalities.
Some people are genetically predisposed to insulin resistance, while other people acquire factors that lead to insulin resistance. Acquired factors, such as excess body fat and physical inactivity, can elicit insulin resistance, and more broadly, clinical metabolic syndrome. Because of this relationship between insulin resistance and metabolic syndrome, it is believed that the underlying causes of this syndrome are obesity, physical inactivity and genetic factors. In fact, most people with insulin resistance and metabolic syndrome have central obesity (excessive fat tissue in and around the abdomen). The biologic mechanisms at the molecular level between insulin resistance and metabolic risk factors are not yet fully understood and appear to be complex.
Metabolic syndrome is typically characterized by a group of metabolic risk factors that include 1) central obesity; 2) atherogenic dyslipidemia (blood fat disorders comprising mainly high triglycerides (“TG”) and low HDL-cholesterol (interchangeably referred to herein as “HDL”) that foster plaque buildups in artery walls); 3) raised blood pressure; 4) insulin resistance or glucose intolerance (the body can't properly use insulin or blood sugar); 5) prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor in the blood); and 6) a proinflammatory state (e.g., elevated high-sensitivity C-reactive protein in the blood). The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines define metabolic syndrome by the following five clinical parameters: a) a waist circumference greater than 102 cm for men, and greater than 88 cm for women; b) a triglyceride level greater than 150 mg/dl; c) an HDL-cholesterol less than 40 mg/dl for men, and less than 50 mg/dl for women; d) a blood pressure greater than or equal to 130/85 mmHG; and e) a fasting glucose greater than 110 mg/dl.
According to the American Heart Association, however, there are no well-accepted criteria for diagnosing the metabolic syndrome. Some guidelines suggest that metabolic syndrome involves four general factors: obesity; diabetes; hypertension; and high lipids. According to the NCEP ATP III guidelines above, the presence of at least three of these five factors meets the medical diagnosis of metabolic syndrome.
Although there is no complete agreement on the individual risk or prevalence of each factor, it is known that the syndrome, as generally agreed upon by those skilled in the field, poses a significant health risk to individuals. A person having one factor associated with the syndrome has an increased risk for having one or more of the others. The more factors that are present, the greater the risks to the person's health. When the factors are present as a group, i.e., metabolic syndrome, the risk for cardiovascular disease and premature death is very high.
For example, a person with the metabolic syndrome is at an increased risk of coronary heart disease, other diseases related to plaque buildups in artery walls (e.g., stroke and peripheral vascular disease), and type 2 diabetes. It is also known that when diabetes occurs, the high risk of cardiovascular complications increases.
Generally, patients suffering from the syndrome are prescribed a change in lifestyle, i.e., an increase in exercise and a change to a healthy diet. The goal of exercise and diet programs is to reduce body weight to within 20% of the “ideal” body weight calculated for age and height.
In some cases, diet and exercise regimens are supplemented with treatments for lipid abnormalities, clotting disorders, and hypertension. For example, patients with the syndrome typically have several disorders of coagulation that make it easier to form blood clots within blood vessels. These blood clots are often a precipitating factor in developing heart attacks. Patients with the syndrome are often placed on daily aspirin therapy to specifically help prevent such clotting events. Furthermore, high blood pressure is present in more than half the people with the syndrome, and in the setting of insulin resistance, high blood pressure is especially important as a risk factor. Some studies have suggested that successfully treating hypertension in patients with diabetes can reduce the risk of death and heart disease by a substantial amount. Additionally, patients have been treated to specifically reduce LDL-cholesterol (interchangeably referred to herein as “LDL”) levels, reduce triglyceride levels, and raise HDL levels. Drug treatment of metabolic syndrome as a whole usually includes treatment with a statin or a combination of a statin with either niacin or a fibrate in order to focus on the factors individually.
Specific treatment of high triglyceride levels with lipid-lowering drugs is intended to inhibit cholesterol synthesis in the liver. Fenofibrate or 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester, which belongs to the fibrate family, has been known for many years as a medicinal active principle because of its efficacy in lowering blood triglyceride and cholesterol levels. Fibrates, such as fenofibrates, supplement the use of lipid-lowering drugs by enhancing catabolism of triglyceride-rich particles and reduce VLDL output. Fibrates also raise HDL and lower triglycerides by activating PPAR-alpha, with upregulated expression of Apo A genes and reduced expression of genes for Apo C-III, PAI-1, and fibrinogen. Fibrates also increase expression of the gene for lipoprotein lipase.
Fibrates are typically orally administered to such patients. A treatment of 30 to 300 mg of fenofibrate per day enables a 20 to 25% reduction of cholesterolemia and a 40 to 50% reduction of triglyceridemia to be obtained.
It is also known that, to obtain a satisfactory hypocholesterolemic effect, it is desirable to maintain a circulating level of fenofibric acid (the active metabolite of fenofibrate). The half-life for elimination of fenofibric acid from the plasma is on the order of 20 hours. Its maximum concentration in the plasma is attained, on average, five hours after ingestion of the medicinal product. The mean concentration in the plasma is on the order of 15 μg/ml for a dose of 300 mg per day. This level is generally stable throughout treatment.
Historically, fenofibrate was available in a pharmaceutical dosage form (Lipidil®) consisting of a hard gelatin capsule containing fenofibrate and pharmaceutically acceptable excipients such as lactose, pregelatinized starch and magnesium stearate. Fenofibrate is also available in another pharmaceutical dosage as Lipidil Micro®. European Patent Application 330,532 and U.S. Pat. No. 4,895,726, both of which are incorporated herein in their entireties, disclose a fenofibrate composition in which the fenofibrate powder is co-micronized with a solid wetting agent or solid surfactant, such as sodium lauryl sulfate. The dosage form exhibits improved dissolution rate and bioavailability of fenofibrate over that of micronized fenofibrate alone or that of micronized fenofibrate subsequently mixed with solid surfactant.
There are no studies that show the use of fibrates only to treat metabolic syndrome as a whole, however. The use of fibrates is only known to treat specific disorders, such as triglyceride levels, and not metabolic syndrome as a whole.
In a study by Ballantyne, C. M., et al, Efficacy of rosuvostatin 10 mg in patients with metabolic syndrome, Am. J. Cardiol (2003), 91:25C-27C, a series of clinical trials showed that fibrate therapy reduces the risk of cardiovascular heart disease. In particular, researchers showed that gemfibrozil reduced the risk for major cardiovascular events in high-risk patients, particularly in those with diabetes and insulin resistance. However, this study only examined the use of gemfibrozil on specific disorders, some of which can be part of metabolic syndrome, and not on metabolic syndrome as a whole.
In a study by Tenebaum, A., et al, Peroxisome proliferators-activated receptor ligand bezafibrate for prevention of type 2 diabetes mellitus in patients with coronary heart disease, Circulation (2004), 109:2197-2202, bezafibrate was shown to significantly lower all-cause and cardiac mortality in patients with triglyceride levels greater than or equal to 200 mg/dl. Bezafibrate treatment also delayed the onset of type 2 diabetes, increased HDL-cholesterol by 16%, and lowered triglycerides by 24%. Tenebaum et al observed the potential for an increase in LDL-cholesterol with fibrate therapy. The Tenebaum study, however, only measures two of the five NCEP ATP III parameters commonly associated with clinical metabolic syndrome, and thus Tenebaum did not, in fact, measure the effect of fibrate on metabolic syndrome. It has been unknown, therefore, whether fibrate is effective in the treatment of the clinical condition of metabolic syndrome, which includes more than the two parameters examined by Tenebaum.
There is an unmet need in the art for a pharmaceutically effective amount of fenofibrate to treat patients having clinically diagnosed metabolic syndrome. Additionally, there is an unmet need in the art to treat patients with fenofibrate for metabolic syndrome as a whole and not just particular elements that can be part of metabolic syndrome.